Yale Team Identifies Key Factor in Stress Effects on the Brain

New Haven, Conn. — Acute and chronic stress can have devastating effects on the brain, and Yale School of Medicine researchers have pinpointed one receptor that plays a key role in that harmful cycle, it was reported this week in the Proceedings of the National Academy of Sciences.

“This could provide new targets for the development of antidepressant medications,” said Ronald Duman, professor of psychiatry and pharmacology and senior author of the study.

Duman said uncontrollable stress is a major contributing factor for neuropsychiatric disorders such as major depression and post-traumatic stress disorders, which have been linked to cellular changes in the hippocampus. The hippocampus is a part of the brain that is particularly susceptible to stress.

But little is known about the underlying mechanisms that block the growth of new neurons, which are needed for antidepressants to be effective in treating depression and anxiety.

The researchers discovered in this mouse study that when activated, the receptor for IL-1ß prevents the brain from creating new neurons. It also decreased the animals’ preference for a sweetened solution, a response that mirrors the inability to feel pleasure that people experience with depression.

IL-1ß is a cytokine—or signaling compound—that promotes inflammation. Previous animal studies showed that exposure to stress increases IL-1ß in several brain areas, including the hippocampus. It also has been demonstrated that administering IL-1ß produces several stress-like effects in the hypothalamus, pituitary, and adrenal system as well as the hippocampus.

The team blocked the effects of IL-1ß with an inhibitor, resulting in blockade of cell cycle arrest.

“This is the first study to show how IL-1ß—when activated by acute and chronic stress—arrests the cell cycle,” said Ronald Duman, professor of psychiatry and pharmacology.

Ja Wook Koo of Yale is lead author of the paper.

The U.S. Public Health Service grants, a Veterans Administration National Center Grant for Post-Traumatic Stress Disorder, and the Connecticut Mental Health Center supported the research.